Abscisic acid (ABA) is an isoprenoid phytohormone discovered in the early 1960's that has received some attention due to its possible medicinal applications (1). Specifically, oral ABA administration has shown prophylactic and therapeutic efficacy in mouse models of diabetes, inflammatory bowel disease (IBD) and atherosclerosis (2-6). In line with ABA's anti-diabetic effects, there is evidence that endogenously generated ABA at nanomolar concentrations can act locally and enhance the insulin-secreting ability of pancreatic β-cells (7). However, little is known about the role of ABA in the modulation of immune and inflammatory responses and the molecular mechanisms underlying its health effects.
Mechanistically, ABA activates peroxisome proliferator-activated receptor γ (PPAR γ) reporter activity in pre-adipocytes (4) and the deficiency of PPAR γ in immune cells impairs the ability of ABA to normalize glucose concentrations and ameliorate macrophage infiltration in the white adipose tissue of obese mice (3). PPAR γ is a nuclear hormone receptor and the molecular target of the thiazolidinedione (TZD) class of anti-diabetic drugs (8). Its naturally occurring and endogenous agonists include fatty acids, eicosanoids and botanicals (9). PPAR γ suppresses the expression of pro-inflammatory cytokines and chemokines by antagonizing the activities of transcription factors, such as AP-1, STAT and NF-κB (10), enhancing nucleocytoplasmic shuttling of the activated p65 subunit of NF-κB (11), and targeting co-repressor complexes on to inflammatory gene promoters via a SUMOylation-driven process (12). These molecular changes induced by PPAR γ agonists are linked to anti-inflammatory efficacy in mouse models of IBD, encephalomyelitis, rheumatoid arthritis and eosinophilic airway inflammation (13-15). There is also clinical evidence showing that rosiglitazone is efficacious in the treatment of mild to moderate ulcerative colitis in humans (16). However, TZDs are unlikely to be adopted for the treatment of chronic inflammation due to their significant side effects, including fluid retention, weight gain and hepatotoxicity (17) that may be linked to their mechanism of action (18). In contrast to TZDs, the ABA-mediated activation of PPAR γ can be blocked by inhibiting intracellular cAMP production or protein kinase A (PKA) activity (2), suggesting that ABA may trigger an alternative mechanism of PPAR γ activation.
The aim of this study was to determine the role of PPAR γ in ABA's immune modulatory properties during LPS-mediated inflammation and influenza-associated inflammation, characterize ABA-controlled gene regulatory networks, and elucidate the mechanisms of action underlying ABA's anti-inflammatory and immunotherapeutic effects.